Summary: Regeneration of tissues following injury can be limited due to the development of strong inflammatory responses that can lead to substantial cell death and inappropriate conditioning of the local environment, which becomes deficient in stimulatory factors and has an excess of inhibitory factors. Our long-term goal is to develop nanoparticles that reprogram the phenotype of monocytes and neutrophils in the blood after trauma, resulting in altered trafficking and anti-inflammatory phenotypes that reduce the extent of damage and may support an environment that leads to enhanced regeneration. The premise of the proposed research is based on our preliminary data indicating the ability to deliver nanoparticles in a minimally invasive manner that target inflammatory monocytes and neutrophils in the blood to reprogram their function, which leads to substantial functional recovery in a spinal cord model. The particles may enhance recovery by multiple mechanisms, including reducing immune cell accumulation at the injury, modulating the splenic microenvironment that is known to coordinate inflammatory responses, or directly inducing an anti-inflammatory or pro-regenerative environment at the injury. The following aims employ nanoparticles with differential binding to monocytes and neutrophils, which influences their phenotype such as trafficking and cytokine production. Importantly, the reprogramming is mediated solely by the physicochemical properties of the nanoparticles (e.g., size, charge, composition) and does not involve an active pharmaceutical ingredient (API), which have been discontinued from many applications due to the risk-benefit ratio. The focus herein is to identify the mechanism by which the particles are enhancing functional recovery, which may also identify design parameters that are more efficient. Aim 1 will investigate nanoparticle association with innate immune cells in circulation, and their subsequent trafficking and phenotype in the inflammatory response. Nanoparticle injection following SCI has led to substantial recovery gains we aim to identify the mechanisms by which the particles are promoting recovery. Particles that induce differential binding, phenotypic polarization, and trafficking of monocytes and neutrophils will be investigated. Aim 2 will investigate the impact of the reprogrammed immune cells on the microenvironment within the spleen and spinal cord. Stromal and immune cells are initially investigated throughout recovery, and we subsequently investigate the extent of axon growth, myelination, and functional recovery. Collectively, these studies will determine the relationship between nanoparticle properties, immune modulation, and the capacity of the environment to reduce damage and enhance functional recovery. We propose that the particles that reprogram based on their physicochemical properties have the potential to be a transformational therapy for trauma by providing a readily available, non-invasive means to reprogram inflammatory monocytes and neutrophils in order to limit damage and enhance regeneration.